Serial Changes in Markers Measuring Coagulation, Fibrinolysis, and Vasoactivity in Patients with Ischemic Stroke

Ischemic stroke (IS) is a heterogeneous disease in which outcome is influenced by many factors. The hemostatic system is activated in association with cerebral ischemia, and thus, markers measuring coagulation, fibrinolysis, and vasoactivity could be useful tools in clinical practice. We investigated whether repeated measurements of these markers reveal patterns that might help in evaluating IS patients, including the early diagnosis of stroke subtypes, in estimating prognosis and risk of recurrence, and in selecting a treatment for secondary prevention of stroke. Vasoconstrictor peptide endothelin-1 (ET-1), homocysteine (Hcy), indicators of thrombin formation and activation (prothrombin fragment 1+2/F1+2, thrombin-antithrombin complex/TAT), indicators of plasmin formation and fibrinolysis (tissue plasminogen activator/t-PA, plasminogen activator inhibitor-1/PAI-1, and D-dimer), and natural anticoagulants (antithrombin/AT, protein C/PC, and protein S/PS) were measured in 102 consecutive mild to moderate IS patients on four occasions: on admission and at 1 week, 1 month, and 3 months after stroke, and once in controls. All patients underwent neurological examination and blood sampling in the same session. Furthermore, 42 IS patients with heterozygous factor V Leiden mutation (FVLm) were selected from 740 IS patients without an obvious etiology, and evaluated in detail for specific clinical, laboratory, and radiological features. Measurements of ET-1 and Hcy levels did not disclose information that could aid in the diagnostic evaluation of IS patients. F1+2 level at 3 months after IS had a positive correlation with recurrence of thromboembolic events, and thus, may be used as a predictive marker of subsequent cerebral events. The D-dimer and AT levels on admission and 1 week after IS were strongly associated with stroke severity, outcome, and disability. The specific analysis of IS patients with FVLm more often revealed a positive family history of thrombosis, a higher prevalence of peripheral vascular disease, and multiple infarctions in brain images, most of which were `silent infarcts´. Results of this study support the view that IS patients with sustained activation of both the fibrinolytic and the coagulation systems and increased thrombin generation may have an unfavorable prognosis. The level of activation may reflect the ongoing thrombotic process and the extent of thrombosis. Changes in these markers could be useful in predicting prognosis of IS patients. A clear need exists for a randomized prospective study to determine whether a subgroup of IS patients with markers indicating activation of fibrinolytic and coagulation systems might benefit from more aggressive secondary prevention of IS.

Exhaled nitric oxide : Variability and association with bronchial hyperresponsiveness and atopy

Airway inflammation is a key feature of bronchial asthma. In asthma management, according to international guidelines, the gold standard is anti-inflammatory treatment. Currently, only conventional procedures (i.e., symptoms, use of rescue medication, PEF-variability, and lung function tests) were used to both diagnose and evaluate the results of treatment with anti-inflammatory drugs. New methods for evaluation of degree of airway inflammation are required. Nitric oxide (NO) is a gas which is produced in the airways of healthy subjects and especially produced in asthmatic airways. Measurement of NO from the airways is possible, and NO can be measured from exhaled air. Fractional exhaled NO (FENO) is increased in asthma, and the highest concentrations are measured in asthmatic patients not treated with inhaled corticosteroids (ICS). Steroid-treated patients with asthma had levels of FENO similar to those of healthy controls. Atopic asthmatics had higher levels of FENO than did nonatopic asthmatics, indicating that level of atopy affected FENO level. Associations between FENO and bronchial hyperresponsiveness (BHR) occur in asthma. The present study demonstrated that measurement of FENO had good reproducibility, and the FENO variability was reasonable both short- and long-term in both healthy subjects and patients with respiratory symptoms or asthma. We demonstrated the upper normal limit for healthy subjects, which was 12 ppb calculated from two different healthy study populations. We showed that patients with respiratory symptoms who did not fulfil the diagnostic criteria of asthma had FENO values significantly higher than in healthy subjects, but significantly lower than in asthma patients. These findings suggest that BHR to histamine is a sensitive indicator of the effect of ICS and a valuable tool for adjustment of corticosteroid treatment in mild asthma. The findings further suggest that intermittent treatment periods of a few weeks’ duration are insufficient to provide long-term control of BHR in patients with mild persistent asthma. Moreover, during the treatment with ICS changes in BHR and changes in FENO were associated. FENO level was associated with BHR measured by a direct (histamine challenge) or indirect method (exercise challenge) in steroid-naïve symptomatic, non-smoking asthmatics. Although these associations could be found only in atopics, FENO level in nonatopic asthma was also increased. It can thus be concluded that assessment of airway inflammation by measuring FENO can be useful for clinical purposes. The methodology of FENO measurements is now validated. Especially in those patients with respiratory symptoms who did not fulfil the diagnostic criteria of asthma, FENO measurement can aid in treatment decisions. Serial measurement of FENO during treatment with ICS can be a complementary or an alternative method for evaluation in patients with asthma.

Search for a Light Higgs Boson in Central Exclusive Diffraction: Method and Detectors

By detecting leading protons produced in the Central Exclusive Diffractive process, p+p → p+X+p, one can measure the missing mass, and scan for possible new particle states such as the Higgs boson. This process augments - in a model independent way - the standard methods for new particle searches at the Large Hadron Collider (LHC) and will allow detailed analyses of the produced central system, such as the spin-parity properties of the Higgs boson. The exclusive central diffractive process makes possible precision studies of gluons at the LHC and complements the physics scenarios foreseen at the next e+e− linear collider. This thesis first presents the conclusions of the first systematic analysis of the expected precision measurement of the leading proton momentum and the accuracy of the reconstructed missing mass. In this initial analysis, the scattered protons are tracked along the LHC beam line and the uncertainties expected in beam transport and detection of the scattered leading protons are accounted for. The main focus of the thesis is in developing the necessary radiation hard precision detector technology for coping with the extremely demanding experimental environment of the LHC. This will be achieved by using a 3D silicon detector design, which in addition to the radiation hardness of up to 5×10^15 neutrons/cm2, offers properties such as a high signal-to- noise ratio, fast signal response to radiation and sensitivity close to the very edge of the detector. This work reports on the development of a novel semi-3D detector design that simplifies the 3D fabrication process, but conserves the necessary properties of the 3D detector design required in the LHC and in other imaging applications.

Search for the Higgs boson produced in association with Z→ℓ+ℓ- using the matrix element method at CDF II

We present a search for associated production of the standard model (SM) Higgs boson and a $Z$ boson where the $Z$ boson decays to two leptons and the Higgs decays to a pair of $b$ quarks in $p\bar{p}$ collisions at the Fermilab Tevatron. We use event probabilities based on SM matrix elements to construct a likelihood function of the Higgs content of the data sample. In a CDF data sample corresponding to an integrated luminosity of 2.7 fb$^{-1}$ we see no evidence of a Higgs boson with a mass between 100 GeV$/c^2$ and 150 GeV$/c^2$. We set 95% confidence level (C.L.) upper limits on the cross-section for $ZH$ production as a function of the Higgs boson mass $m_H$; the limit is 8.2 times the SM prediction at $m_H = 115$ GeV$/c^2$.

Mass spectrometry and n-in-one analytics in early drug discovery: Combinatorial chemistry libraries, lipophilicity and absorption screening

This thesis describes current and past n-in-one methods and presents three early experimental studies using mass spectrometry and the triple quadrupole instrument on the application of n-in-one in drug discovery. N-in-one strategy pools and mix samples in drug discovery prior to measurement or analysis. This allows the most promising compounds to be rapidly identified and then analysed. Nowadays properties of drugs are characterised earlier and in parallel with pharmacological efficacy. Studies presented here use in vitro methods as caco-2 cells and immobilized artificial membrane chromatography for drug absorption and lipophilicity measurements. The high sensitivity and selectivity of liquid chromatography mass spectrometry are especially important for new analytical methods using n-in-one. In the first study, the fragmentation patterns of ten nitrophenoxy benzoate compounds, serial homology, were characterised and the presence of the compounds was determined in a combinatorial library. The influence of one or two nitro substituents and the alkyl chain length of methyl to pentyl on collision-induced fragmentation was studied, and interesting structurefragmentation relationships were detected. Two nitro group compounds increased fragmentation compared to one nitro group, whereas less fragmentation was noted in molecules with a longer alkyl chain. The most abundant product ions were nitrophenoxy ions, which were also tested in the precursor ion screening of the combinatorial library. In the second study, the immobilized artificial membrane chromatographic method was transferred from ultraviolet detection to mass spectrometric analysis and a new method was developed. Mass spectra were scanned and the chromatographic retention of compounds was analysed using extract ion chromatograms. When changing detectors and buffers and including n-in-one in the method, the results showed good correlation. Finally, the results demonstrated that mass spectrometric detection with gradient elution can provide a rapid and convenient n-in-one method for ranking the lipophilic properties of several structurally diverse compounds simultaneously. In the final study, a new method was developed for caco-2 samples. Compounds were separated by liquid chromatography and quantified by selected reaction monitoring using mass spectrometry. This method was used for caco-2 samples, where absorption of ten chemically and physiologically different compounds was screened using both single and nin- one approaches. These three studies used mass spectrometry for compound identification, method transfer and quantitation in the area of mixture analysis. Different mass spectrometric scanning modes for the triple quadrupole instrument were used in each method. Early drug discovery with n-in-one is area where mass spectrometric analysis, its possibilities and proper use, is especially important.

Top Quark Mass Measurement in the lepton+jets Channel Using a Matrix Element Method and in situ Jet Energy Calibration

A precision measurement of the top quark mass m_t is obtained using a sample of ttbar events from ppbar collisions at the Fermilab Tevatron with the CDF II detector. Selected events require an electron or muon, large missing transverse energy, and exactly four high-energy jets, at least one of which is tagged as coming from a b quark. A likelihood is calculated using a matrix element method with quasi-Monte Carlo integration taking into account finite detector resolution and jet mass effects. The event likelihood is a function of m_t and a parameter DJES to calibrate the jet energy scale /in situ/. Using a total of 1087 events, a value of m_t = 173.0 +/- 1.2 GeV/c^2 is measured.

Top quark mass measurement in the lepton plus jets channel using a modified matrix element method

We report a measurement of the top quark mass, m_t, obtained from ppbar collisions at sqrt(s) = 1.96 TeV at the Fermilab Tevatron using the CDF II detector. We analyze a sample corresponding to an integrated luminosity of 1.9 fb^-1. We select events with an electron or muon, large missing transverse energy, and exactly four high-energy jets in the central region of the detector, at least one of which is tagged as coming from a b quark. We calculate a signal likelihood using a matrix element integration method, with effective propagators to take into account assumptions on event kinematics. Our event likelihood is a function of m_t and a parameter JES that determines /in situ/ the calibration of the jet energies. We use a neural network discriminant to distinguish signal from background events. We also apply a cut on the peak value of each event likelihood curve to reduce the contribution of background and badly reconstructed events. Using the 318 events that pass all selection criteria, we find m_t = 172.7 +/- 1.8 (stat. + JES) +/- 1.2 (syst.) GeV/c^2.

Measurement of the top quark mass at CDF using the “neutrino ϕ weighting” template method on a lepton plus isolated track sample

We present a measurement of the top quark mass with t-tbar dilepton events produced in p-pbar collisions at the Fermilab Tevatron $\sqrt{s}$=1.96 TeV and collected by the CDF II detector. A sample of 328 events with a charged electron or muon and an isolated track, corresponding to an integrated luminosity of 2.9 fb$^{-1}$, are selected as t-tbar candidates. To account for the unconstrained event kinematics, we scan over the phase space of the azimuthal angles ($\phi_{\nu_1},\phi_{\nu_2}$) of neutrinos and reconstruct the top quark mass for each $\phi_{\nu_1},\phi_{\nu_2}$ pair by minimizing a $\chi^2$ function in the t-tbar dilepton hypothesis. We assign $\chi^2$-dependent weights to the solutions in order to build a preferred mass for each event. Preferred mass distributions (templates) are built from simulated t-tbar and background events, and parameterized in order to provide continuous probability density functions. A likelihood fit to the mass distribution in data as a weighted sum of signal and background probability density functions gives a top quark mass of $165.5^{+{3.4}}_{-{3.3}}$(stat.)$\pm 3.1$(syst.) GeV/$c^2$.

New Method for Delexicalization and its Application to Prosodic Tagging for Text-to-Speech Synthesis

This paper describes a new flexible delexicalization method based on glottal excited parametric speech synthesis scheme. The system utilizes inverse filtered glottal flow and all-pole modelling of the vocal tract. The method provides a possibil- ity to retain and manipulate all relevant prosodic features of any kind of speech. Most importantly, the features include voice quality, which has not been properly modeled in earlier delex- icalization methods. The functionality of the new method was tested in a prosodic tagging experiment aimed at providing word prominence data for a text-to-speech synthesis system. The ex- periment confirmed the usefulness of the method and further corroborated earlier evidence that linguistic factors influence the perception of prosodic prominence.

Every method counts

In this study we explore the concurrent, combined use of three research methods, statistical corpus analysis and two psycholinguistic experiments (a forced-choice and an acceptability rating task), using verbal synonymy in Finnish as a case in point. In addition to supporting conclusions from earlier studies concerning the relationships between corpus-based and ex- perimental data (e. g., Featherston 2005), we show that each method adds to our understanding of the studied phenomenon, in a way which could not be achieved through any single method by itself. Most importantly, whereas relative rareness in a corpus is associated with dispreference in selection, such infrequency does not categorically always entail substantially lower acceptability. Furthermore, we show that forced-choice and acceptability rating tasks pertain to distinct linguistic processes, with category-wise in- commensurable scales of measurement, and should therefore be merged with caution, if at all.

A Method for Comparing Scholarly Journals as Service Providers to Authors

When authors of scholarly articles decide where to submit their manuscripts for peer review and eventual publication, they often base their choice of journals on very incomplete information abouthow well the journals serve the authors’ purposes of informing about their research and advancing their academic careers. The purpose of this study was to develop and test a new method for benchmarking scientific journals, providing more information to prospective authors. The method estimates a number of journal parameters, including readership, scientific prestige, time from submission to publication, acceptance rate and service provided by the journal during the review and publication process. Data directly obtainable from the web, data that can be calculated from such data, data obtained from publishers and editors, and data obtained using surveys with authors are used in the method, which has been tested on three different sets of journals, each from a different discipline. We found a number of problems with the different data acquisition methods, which limit the extent to which the method can be used. Publishers and editors are reluctant to disclose important information they have at hand (i.e. journal circulation, web downloads, acceptance rate). The calculation of some important parameters (for instance average time from submission to publication, regional spread of authorship) can be done but requires quite a lot of work. It can be difficult to get reasonable response rates to surveys with authors. All in all we believe that the method we propose, taking a “service to authors” perspective as a basis for benchmarking scientific journals, is useful and can provide information that is valuable to prospective authors in selected scientific disciplines.